LAM, the pulmonary manifestation of tuberous sclerosis complex (TSC), is an often-fatal disease which is characterized by the widespread proliferation of abnormal smooth muscle cells that grow aberrantly in the lung, producing cystic changes within the lung parenchyma (Sullivan, E. J., Chest, 114: 1689-1703 (1998)). For reasons that are not clearly understood, LAM affects women almost exclusively. LAM affects 30-40% of women with TSC (Costello, L. C. et al., Mayo Clin. Proc. 75: 591-594 (2000); Franz, D. N. et al., Am. J. Respir. Crit. Care Med., 164: 661-668 (2001)). LAM can also occur, in women who do not have clinical manifestations of TSC, as well as those who do not have germline mutations in TSC1 or TSC2 (sporadic LAM).
The lungs in LAM are diffusely infiltrated by histologically benign, immature-appearing smooth muscle cells that express estrogen receptor (ER) alpha and progesterone receptor. This cellular infiltration is accompanied by cystic lung degeneration. Most women with TSC-associated LAM and 60% of women with sporadic LAM have renal angiomyolipomas (AMLs), which contain abnormal smooth muscle cells that are virtually identical to LAM cells. The relentless growth of LAM cells in the pulmonary airway, parenchyma, lymphatics and blood vessels leads to respiratory failure and death. In a Mayo Clinic series, LAM was the third most frequent cause of TSC-related death, after renal disease and brain tumors (Shepherd, C. W. et al., Mayo Clin. Proc., 66: 792-796 (1991)).
Genetic studies by the present inventors and others have revealed that LAM cells from both TSC-LAM and sporadic LAM carry inactivating mutations in both alleles of the TSC1 or TSC2 genes, and spread to the lungs via a metastatic mechanism despite the fact that LAM cells have a histologically benign appearance. Genetic evidence for this “benign metastasis” model of LAM has arisen from women with the sporadic form of LAM, who have somatic TSC2 mutations in LAM cells and renal AML cells but not in normal kidney, lung, or peripheral blood cells (Yu, J. et al., Am. J. Respir. Crit. Care Med., 164: 1537-1540 (2001); Carsillo, T., Proc. Natl. Acad. Sci. USA, 97: 6085-6090 (2000)); and fluorescent in situ hybridization analysis of LAM that recurs after lung transplantation (Karbowniczek, M. et al., Am. J. Respir. Crit. Care Med., 167: 976-982 (2003)). The presence of disseminated neoplastic cells has been detected in blood and body fluids from LAM patients (Crooks, D. M. et al., Proc. Natl. Acad. Sci. USA, 101: 17462-17467 (2004)).
The protein products of TSC1 and TSC2, hamartin and tuberin, respectively, form heterodimers (Plank, T. L. et al., Cancer Res., 58: 4766-4770 (1998); van Slegtenhorst, M. et al., Hum. Mol. Genetc., 7: 1053-1057 (1998)) that inhibit the small GTPase Ras homologue enriched in brain (Rheb), via tuberin's highly conserved GTPase activating domain. In its active form, Rheb activates the mammalian target of rapamycin (mTOR) complex 1 (TORC1), which is a key regulator of protein translation, cell size, and cell proliferation (Crino, P. B., N. Engl. J. Med., 355: 1345-1356 (2006). Evidence of OTRC1 activation, including hyperphosphorylation of ribosomal protein S6, has been observed in tumor specimens from TSC patients and LAM patients (El-Hashemite, N. et al., Lancet, 361: 1348-1349 (2003); Karbowniczek, M. et al., Am. J. Pathol., 162: 491-500 (2003); Yu. J., Am. J. Physiol. Lung Cell Mol. Physiol., 286: L694-700 (2004)). Independent of its activation of mTOR, Rheb inhibits the activity of B-Raf and C-Raf/Raf-1 kinase, resulting in reduced phosphorylation of p42/44 MAPK (Im. E. et al., Oncogene, 21: 6356-6365 (2002); Karbowniczek, M. et al., J. Biol. Chem., 279: 29930-29937 (2004); Karbowniczek, M. et al., J. Biol. Chem., 281: 25447-25456 (2006)), but the impact of the Raf/MEK/MAPK pathway on disease pathogenesis is undefined.
The female predominance of LAM, coupled with the genetic data indicating that LAM cells are metastatic, suggests that estrogen may promote the metastasis of tuberin-null cells. Both LAM cells and angiomyolipoma cells express estrogen receptor alpha (Logginidou, H. et al., Chest., 117: 25-30 (2000)), and there are reports of symptom mitigation in LAM patients after oophorectomy and worsening of symptoms during pregnancy (Sullivan, E. J. et al., supra). However, the molecular and cellular mechanisms that may underlie an impact of estrogen on the metastasis of LAM cells are not well defined, in part because of the lack of in vivo models that recapitulate the metastatic behavior of LAM cells.
Oxygen therapy may become necessary if the disease continues to worsen and lung function is impaired. Lung transplantation is considered as a last resort.
Although the immunosuppressant drug sirolimus (rapamycin) has shown preliminary promise as a potential LAM therapy, there is no currently approved drug for the treatment or prophylaxis of LAM.
New therapies and preventatives are clearly needed for LAM and related pathologies of similar etiology.